BLR&D Research Career Scientist Award application

我的研究工作主要是探索潜在的生理问题，关于微小的囊泡， 外来体这些外泌体从许多不同类型的细胞或食物来源的外泌体样细胞释放。 我正在VA患者中研究外泌体作为治疗载体在VA患者中的有希望的作用， 为不同但特定的一组医学状况提供治疗，即，肥胖/糖尿病，非酒精性 脂肪肝（NASH）和癌症。有大量的退伍军人谁是肥胖和/或 得了癌症肥胖和癌症给依赖退伍军人管理局护理的退伍军人带来了特殊的负担。肥胖 每年导致超过30万人死亡，并增加NASH、2型糖尿病和几种糖尿病的风险。 包括结肠癌前列腺癌和肾癌。自从获得我最初的研究职业科学家奖以来，我的 研究小组发表了50多篇关于这一主题的论文。总的来说，我们的发现支持了 我的团队继续资助研究以下3个目标：（1）肿瘤外泌体在以下方面发挥作用：（a） 通过诱导髓源性抑制细胞、抑制树突细胞 （B）通过分选抑制性miRNA， 肿瘤细胞转化为基于致癌主要穹窿蛋白（MVP）的外泌体，肿瘤生长更快（Nature 通讯2017年2月17日;8：14448，自然通讯。2015;6：6956）;以及（c）最近，我们 发现了一种新的纳米颗粒（Oncotarget. 2016年5月12日）。与其他电动汽车不同，这种细胞外纳米囊泡 （命名为HG-NV，HG-NV代表HomoGenous nanovesicle以及Huang-Ge- nanovesicle） 来自小鼠和人乳腺肿瘤细胞的细胞富含RNA。肿瘤来源的HG-NV更多 比外泌体更能促进肿瘤进展。分子主要存在于乳腺肿瘤HG- 已经识别和表征了NV。这一发现可能对推进这两个方面都有意义。 微泡生物学研究和临床管理，包括作为生物标志物的潜在用途，（2）。外来体 从非肿瘤细胞释放的外泌体在以下方面发挥作用：（a）脂肪组织外泌体样囊泡介导 巨噬细胞诱导的胰岛素抵抗（糖尿病. 2009 Nov;58（11）：2498-505）;（B）我们还发现， 肠粘液来源外泌体介导Wnt/β-catenin信号传导激活并在诱导中发挥作用 肝NKT细胞无反应性（Hepatology，2013 57（3）：1250-61）;和（c）肠粘液来源的外泌体携带 前列腺素E2和抑制肝NKT细胞的活化（J Immunol，2013，190（7）：3579-89）;（3）.外泌体- 类似于来自可食用植物的纳米颗粒对哺乳动物细胞具有作用和治疗应用：（a）我们 使用小鼠模型表明，植物和小鼠肠道宿主细胞之间的种间交流， 通过诱导抗炎基因表达的可食用植物来源的外泌体样纳米颗粒 细胞因子，抗氧化和Wnt信号的激活，这对维持肠道 体内平衡这一发现不仅开辟了一个新的途径，调查ELN作为一种手段，以防止 肝脏相关疾病的发展，如酒精引起的肝损伤，但揭示了研究 通过可食用植物在肝脏中进行种间交流的细胞和分子机制- 衍生的纳米颗粒;（B）靶向药物/治疗性miRNA（Nature Communications. 2013;4：1867）交付 肠巨噬细胞、脑小胶质细胞（Molecular therapy：2015，Volume 24，Issue 1，p96-105）和 （c）西兰花- 衍生纳米颗粒通过激活树突状细胞AMP活化蛋白激酶抑制小鼠结肠炎 （分子疗法。2017年，出版中）;和（d）葡萄外泌体样纳米颗粒诱导肠干细胞 并保护小鼠免受DSS诱导的结肠炎（Molecular Therapy. 2013年7月;21（7）：1345-57）。

My research work largely explores the underlying physiologic questions regarding tiny vesicles called exosomes. These exosomes are released from many different types of cells or food-derived exosome-like nanoparticles and I am investigating in VA patients the promising role of exosomes as therapeutic vehicles in delivering treatment for a diverse but specific group of medical conditions, i.e.,obesity/diabetes, Nonalcoholic fatty liver disease (NASH), and cancer. There is a substantial population of veterans who are obese and/or have cancer. Obesity and cancer pose special burdens on veterans who depend on VA care. Obesity contributes to over 300,000 deaths per year and increases the risk of NASH, type 2 diabetes, and several cancers including colon, prostate, and kidney. Since receiving my initial Research Career Scientist award, my research group has published more than 50 manuscripts on this subject. Collectively, our findings support continued funding of my team to investigate the following 3 aims: (1) Tumor exosomes play a role in: (a) immunosuppression through induction of myeloid-derived suppressor cells, inhibition of dendritic cell differentiation, and inhibition of activation of NK cell immunotherapy; (b) by sorting suppressor miRNAs from tumor cells into exosomes based on the oncogenic major vault protein (MVP), tumors grow faster (Nature Communications. 2017 Feb 17;8:14448, Nature communications. 2015;6:6956); and (c) more recently, we discovered a novel nanoparticle (Oncotarget. 2016 May 12). Unlike other EVs, this extracellular nanovesicle (named HG-NV, HG-NV stands for HomoGenous nanovesicle as well as for Huang-Ge- nanovesicle) released from both mouse and human breast tumor cells is enriched with RNAs. Tumor-derived HG-NVs are more potent in promoting tumor progression than exosomes. Molecules predominantly present in breast tumor HG- NVs have been identified and characterized. This discovery may have implications in advancing both microvesicle biology research and clinical management including potential useas a biomarker, (2). Exosomes released from non-tumor cells play a role in: (a) adipose tissue exosome-like vesicles mediating activation of macrophage-induced insulin resistance (Diabetes. 2009 Nov;58(11):2498-505); (b) we also found that intestinal mucus-derived exosomes mediate activation of Wnt/β-catenin signaling and play a role in induction of liver NKT cell anergy (Hepatology, 2013 57(3):1250-61); and (c) intestinal mucus‐derived exosomes carry prostaglandin E2 and suppress activation of liver NKT cells (J Immunol, 2013, 190(7):3579-89); (3). Exosome- like nanoparticles from edible plants have an effect and therapeutic application on mammalian cells: (a) we used mouse models to show that interspecies communication between plant and mouse gut host cells through edible plant derived exosome‐like nanoparticles by inducing expression of genes for anti-inflammation cytokines, antioxidation, and activation of Wnt signaling, which are crucial for maintaining intestinal homeostasis. This finding not only opens up a new avenue for investigating ELNs as a means to protect against the development of liver related diseases such as alcohol induced liver damage, but sheds light on studying the cellular and molecular mechanisms underlying inter-species communication in the liver via edible plant- derived nanoparticles; (b) targeted drug/therapeutic miRNAs (Nature Communications. 2013;4:1867) delivery to intestinal macrophages, brain microglia cells (Molecular therapy: 2015, Volume 24, Issue 1, p96–105) and inflammatory tumor sites (Cancer Research, 2015;75:2520-9) by grapefruit ELN is possible; (c) Broccoli- Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase (Molecular Therapy. 2017, in press); and (d) Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis (Molecular Therapy. 2013 Jul;21(7):1345-57).